Sphingosine-1-phosphate (hereinafter, abbreviated as “S1P”) represented by formula (A) is a lipid that is synthesized by the intracellular metabolic turnover of sphingolipids or the extracellular action of secretory sphingosine kinase. It is pointed out that S1P acts as an intercellular and intracellular messenger (Biochem. Pharm., 58, 201 (1999))

As receptors of S1P, EDG-1 which is a G-protein coupled receptor and its analogous molecules, EDG-3, EDG-5, EDG-6 and EDG-8 (also called S1P1, S1P3, S1P2, S1P4, and S1P5, respectively) are known. They are called EDG family together with EDG-2, EDG-4 and EDG-7 which are receptors of lysophosphatidic acid (LPA). S1P receptors binds to S1P and deliver signals into cells via G-protein coupled with the receptors. Gs, Gi, Gq and G12/13 etc. are known as G-proteins to which S1P receptor can couple, and it is considered that the receptor is involved in responses such as increase of cell proliferation, suppression of cell proliferation, induction of cell chemotaxis, and inhibition of cell chemotaxis.
As biological action of S1P, inhibition of migration of smooth muscle cells or cancer cells, platelet aggregation, induction of cell chemotaxis, inhibition of cell chemotaxis and the like are known in vitro experiments, and as the results of in vivo experiments, it is known that S1P shows effects of controlling blood pressure, promoting angiogenesis, reducing renal blood flow, inhibiting lung fibrosis, promoting the lymphocyte homing into lymphatic organs, and the like. It is considered that those various physiological effects are mediated by S1P receptors existing in cell membrane. However, it has been scarcely clarified excluding some cases which subtypes of S1P receptors mediate these effects in practice.
Recently, from the study for EDG-1 knock-out mice, it is strongly indicated that S1P induced angiogenesis via EDG-1 (J Clin. Invest., 106, 951 (2000)). Therefore, it is suggested that an EDG-1 agonist is used as an agent for treating diseases caused by anangioplasia. For example, it is used as an agent for prevention and/or treatment of peripheral arterial disease such as arteriosclerosis obliterans, thromboangiitis obliterans, Buerger's disease, or diabetic neuropathy; varicose vein such as hemorrhoid, anal fissure, or anal fistula; dissecting aneurysm of the aorta, sepsis, inflammatory disease such as angiitis, nephritis, or pneumonia, various edematous disease involved in ischemia of various organ and increase of the blood permeability, for example, cerebral infarction, myocardial infarction, angina, congestive heart failure, pleuritis, DIC (disseminated intravascular coagulation), or multiple organ failure. In addition, angioplasty is closely related to osteogenesis, so the EDG-1 agonist can also be used as a treating agent for abnormal bone metabolism such as osteoporosis. In addition, from the study for the knock-out mice, it is also indicated that there is a possibility that EDG-1 inhibited migration of a vascular smooth muscle. Therefore, the EDG-1 agonist can also be used as an agent for prevention and/or treatment of arteriosclerosis. In addition, the EDG-1 agonist can also be used as an agent for enhancing wound healing of cornea, skin, digestive organs, or the like, or, for example, as an agent for prevention and/or treatment of bedsore, burn, ulcerative colitis, Crohn's disease, or the like. Further, the EDG-1 agonist can also be used as a preoperative, postoperative, and/or prognostic activator for blood vessel accompanying transplantation of various organs, for example, as an adhesion activator of transplanted organs such as heart transplantation, renal transplantation, dermal transplantation or liver transplantation.
In addition, the S1P is known to be effective to mouse bleomycin-elicited pulmonary fibrosis (see, WO 01/03739). Therefore, the S1P agonist can be used as an agent for prevention and/or treatment of diseases caused by fibrosis of various organs, for example, fibrosis including pulmonary fibrosis, liver fibrosis, and the like, interstitial pneumonitis, chronic pepatitis, liver cirrhosis, chronic renal insufficiency, and renal glomerular sclerosis.
In addition, it was reported that the S1P acts to promote secretion of insulin from a pancriatic β cell via EDG-3, and that the S1P inhibits glucagon-dependent insulin secretion via EDG-1 (see, for example, Endocrine Journal, 47(3), 261, (2000) and Diabetes, 52, 1986, (2003)). Thus, an EDG-1 agonist may be used as an agent for prevention and/or treatment of diabetes, in particular, as a glucose metabolism-improving agent, an insulin secretion-promoting agent, or a pancriatic cell-protecting agent.
On the other hand, EDG-6 is localized and strongly expressed in cells and organs of the lymphatic and hematopoietic systems including spleen, leukocytes, lymph gland, thymus, bone marrow, lung and the like, which suggests the possibility that the EDG-6 is closely related to the effects of S1P in the course of inflammation or in the immune system (Biochem. Biophys. Res. Commun., 268, 583 (2000)).
Moreover, it is known that the EDG-6 polypeptide or its homologue is involved in immunomodulation, antiinflammation and the like in a similar manner as EDG-1, which brings about the potential usability of those substances in treating autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis and the like), allergic diseases (e.g., atopic dermatitis and the like), asthma, inflammatory diseases, infection, ulcer, lymphoma, malignant tumor (e.g., cancer and the like), leukemia, arteriosclerosis, multiple organ failure, diseases associated with lymphocyte infiltration into a tissue (e.g., reperfusion injury after ischemia, and the like), and the like.
From these findings, a drug which acts on EDG-1 and/or EDG-6 is thought to be useful as an agent for prevention and/or treatment of: a peripheral arterial disease such as arteriosclerosis obliterans, thromboangiitis obliterans, Buerger's disease, or diabetic neuropathy; varicose vein such as hemorrhoid, anal fissure, or anal fistula; dissecting aneurysm of the aorta; sepsis; an inflammatory disease such as angiitis, nephritis, or pneumonia; various edematous disease involved in ischemia of various organs and increase of the blood permeability, for example, cerebral stroke, ischemia-reperfusion injury, cerebral infarction, myocardial infarction, angina, congestive heart failure, pleuritis, DIC, or multiple organ failure; bedsore; burn; trauma injury; inflammatory bowel disease; genetic disease; osteoporosis; arteriosclerosis; fibrosis including pulmonary fibrosis, liver fibrosis, and the like; interstitial pneumotitis; chronic hepatitis; liver cirrhosis; chronic renal insufficiency; renal glomerular sclerosis; diabetes; rejection in transplantation; rejection of a transplanted organ; graft versus host disease; an autoimmune disease (e.g., systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, psoriasis, ulcerative colitis, Crohn's disease, myasthenia gravis, autoimmune diabetes, and the like); an allergic disease (e.g., atopic dermatitis, pollen disease, food allergy, and the like); asthma; infectious disease; ulcer; lymphoma; malignant tumor (e.g., cancer and the like); leukemia; a disease associated with lymphocyte infiltration into a tissue; and the like. In addition, those drugs are thought to be useful as a preoperative, postoperative, and/or prognostic activator for blood vessel accompanying transplantation of various organs, tissues, and/or cells, for example, as an adhesion activator of transplanted organs such as heart transplantation, renal transplantation, dermal transplantation or liver transplantation.
Recently, it was reported that an EDG-1 agonist which selectively binds to EDG-1 as compared with EDG-3 at least 20 folds was effective for immune disorder (see, WO 03/061567).
On the other hand, it is disclosed that a carboxylic acid derivative represented by formula (Z):
wherein R1Z represents C1-8 alkyl, C1-8 alkoxy, a halogen atom, nitro, or trifluoromethyl; ring AZ represents a C5-7 monocyclic carbocyclic group or a 5- to 7-membered monocyclic heterocyclic group containing one or two nitrogen atoms, one oxygen atom and/or one sulfur atom; EZ represents —CH2—, —O—, —S— or —NR6Z—, in which R6Z represents a hydrogen atom or C1-8 alkyl; R2Z represents C1-8 alkyl, C1-8 alkoxy, a halogen atom, nitro or trifluoromethyl; R3Z represents a hydrogen atom or C1-8 alkyl; R4Z represents a hydrogen atom or C1-8 alkyl, or R2Z and R4Z may be taken together to form —CH2CH2— or —CH═CH—; GZ represents —CONR7Z—, —NR7ZCO—, —SO2NR7Z—, —NR7ZSO2—, —CH2NR7Z- or —NR7ZCH2—, in which R7Z represents a hydrogen atom, C1-8 alkyl or the like; QZ represents C1-4 alkylene or the like; pZ represents 0 or an integer of 1 to 5; qZ represents an integer of 4 to 6; rZ represents 0 or an integer of 1 to 4; and  represents a single bond or a double bond, a prodrug thereof, or a non-toxic salt thereof is useful as an EDG-1 agonist (see WO 02/092068).
Moreover, it is disclosed that a compound represented by formula (Y):
wherein ring AY represents a cyclic group; ring BY represents a cyclic group which may further have a substituent(s); XY represents a bond or a spacer having 1 to 8 atoms in its main chain in which one atom in the spacer may be taken together with a substituent on ring BY to form a ring group which may have a substituent(s); YY represents a bond or a spacer having 1 to 10 atoms in its main chain in which one atom in the spacer may be taken together with a substituent on ring BY to form a ring group which may have a substituent(s); ZY represents an acidic group which may be protected; nY represents 0 or 1, wherein when nY is O, mY represents 1 and R1Y represents a hydrogen atom or a substituent, and when nY is 1, mY is 0 or an integer of 1 to 7 and R1Y represents a substituent in which when mY is 2 or more, a plurality of R1Ys are the same or different from each other, a salt thereof, a solvate thereof, or a prodrug thereof has an S1P receptor binding ability (see WO 2005/020882).
Moreover, it is disclosed that a compound represented by formula (S):
wherein ArS represents phenyl or naphthyl; AS represents carboxy, or the like; ns represents 2, 3 or 4; R1S and R2S each independently represents a hydrogen atom, a halogen atom, hydroxy, carboxy, C1-6 alkyl which may be substituted by 1 to 3 halogen atoms, or phenyl which may be substituted by 1 to 3 halogen atoms; R3S represents a hydrogen atom or C1-4 alkyl which may be substituted by 1 to 3 hydroxy or halogen atoms; R4Ss each independently represents hydroxy, a halogen atom, carboxy, or the like; CS represents C1-8 alkyl, C1-8 alkoxy, phenyl, or the like or CS is nil; and BS represents phenyl, C5-16 alkyl, or the like (only necessary parts of the definitions of the symbols are extracted);
a pharmaceutically acceptable salt thereof and a hydrate thereof, and
a compound represented by formula (T):
wherein ArT represents phenyl or naphthyl; AT represents carboxy, or the like; mT represents 0 or 1; nT represents 0 or 1; R1T and R2T each independently represents a hydrogen atom, a halogen atom, hydroxy, carboxy, C1-4 alkyl or phenyl which may be substituted by a halogen atom, or the like; R3T represents a hydrogen atom, C1-4 alkyl which may be substituted by hydroxy or a halogen atom, or the like; R4Ts each independently represents a halogen atom, C1-4 alkyl, C1-3 alkoxy, or the like; CT represents C1-8 alkyl, C1-8 alkoxy, phenyl, or the like or CT is nil; and BT represents phenyl, C5-16 alkyl, or the like (only necessary parts of the definitions of the symbols are extracted);
a pharmaceutically acceptable salt thereof, and a hydrate thereof are useful as EDG-1 agonists (see WO 03/062248 and WO 03/062252).
Moreover, it is known that a compound represented by formula (B):
is an EDG-1-selective agonist (see, J. Biol. Chem., 279, 13839 (2004)).
In addition, various compounds each having an agonistic activity against EDG-1 are disclosed (see, WO 03/062392 and WO 04/009816).
In addition, it is disclosed that a compound having a dihydronaphthalene skeleton and represented by formula (U):
wherein XU and YU each independently represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, alkyl having 4 or less carbon atoms, or alkoxyl having 4 or less carbon atoms, and ZU represents a secondary or tertiary amine (only necessary parts of the definitions of the symbols are extracted),is useful as an analgesic or a tranquilizer (see, U.S. Pat. No. 4,022,791).
Similarly, there is disclosed a bacteriocide composition containing an organic amine compound represented by formula (W):
wherein one of XW and YW represents a hydrogen atom while the other represents the following:
provided that RW represents a hydrogen atom, methyl, or ethyl; ZW represents a hydrogen atom, C1-4 alkyl, or the like; R1W and R2W each represent a hydrogen atom or C1-4 alkyl, or R1W and R2W each represent an optionally-substituted heterocyclic group together with a nitrogen atom adjacent thereto; and nW represents 0 or 1 (only necessary parts of the definitions of the symbols are extracted);
a stereoisomer of the compound; or an acid addition salt thereof (see JP-A-61-291576).
In addition, it is disclosed that an N-cycloalkyl-[ω-(3,4-dihydro-2-naphthalenyl)alkyl]amine derivative represented by formula (VV):
wherein R1V and R2V each represent a hydrogen atom, a halogen atom, alkyl, or the like, or R1V and R2V together form ethylenoxy, trimethilene, or the like; R3V represents a hydrogen atom, a halogen atom, alkyl, or the like; R4V represents a hydrogen atom, alkyl, acyl, or the like; R5V represents cycloalkyl; and pV represents an integer of 2 to 6 (only necessary parts of the definitions of the symbols are extracted)
is useful as a treating agent for pollakiuria and acraturesis (see JP-A-10-120632).
In addition, it is disclosed that an amine compound represented by formula (X):
wherein ArX represents an aromatic ring assembly group or a fused aromatic ring; XX represents (i) a bond, (ii) —S—, (iii) C1-6 alkylene or the like which may have 1 to 3 substituents selected from the group consisting of oxo and C1-6 alkyl, (iv) —CO—O—, or (v) —(CH2)pX—X1X, or the like; YX represents a divalent C1-6 aliphatic hydrocarbon group; R1X and R2X each represent a hydrogen atom or lower alkyl, or R1X and R2X together form a nitrogen-containing heterocyclic group; ring AX represents a benzene ring; and ring BX represents a 4- to 8-membered ring (only necessary parts of the definitions of the symbols are extracted)
is useful as an inhibitor of production or secretion of amyloid β protein (see WO 98/038156).